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Journal of Psychopharmacology
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Effect of the ß3 adrenoceptor agonist CL 316243 on hypothalamic 5-HT synthesis and suppression of REM sleep in the rat

R.K. Conley

In Vivo Neuroscience Department, The Neuroscience Research Centre, Merck Sharp & Dohme, Harlow, Essex, UK, rachel.conley{at}pfizer.com

J. Li

In Vivo Neuroscience Department, The Neuroscience Research Centre, Merck Sharp & Dohme, Harlow, Essex, UK

M. Ivarsson

In Vivo Neuroscience Department, The Neuroscience Research Centre, Merck Sharp & Dohme, Harlow, Essex, UK

P.H. Hutson

In Vivo Neuroscience Department, The Neuroscience Research Centre, Merck Sharp & Dohme, Harlow, Essex, UK

ß3 adrenoceptor agonists show an antidepressant-like profile in preclinical rodent assays and improve mood in clinically-obese patients. These observations suggest a possible antidepressant utility for ß3 adrenoceptor agonists. The present study examined the effects of acute and chronic administration of the ß3 adrenoceptor agonist CL 316243 on two physiological indicators of antidepressant activity in the rat: hypothalamic 5-HT synthesis and suppression of REM sleep. 5-HT synthesis was estimated by the accumulation of 5-hydroxytryptophan (5-HTP) after treatment with the L-aromatic acid decarboxylase inhibitor NSD 1015. Sleep-wake patterns were monitored using electroencephalogram and electromyogram signals collected by radiotelemetry. Rats were administered CL 316243 acutely or once daily for 11 days. Acute administration of CL 316243 significantly increased hypothalamic 5-HT synthesis, as indicated by increased levels of 5-HTP, and reduced the amount of REM sleep. However, chronic administration produced no changes in 5-HTP or REM compared with vehicle treatment. The present observations suggest that acute administration of CL 316243 causes antidepressant-like effects on REM sleep, possibly mediated by increased central 5-HT synthesis. However, these effects are not maintained with repeated dosing.

Key Words: ß3 adrenoceptor • REM sleep • 5-HT synthesis • hypothalamus • rat • depression

This version was published on August 1, 2007

Journal of Psychopharmacology, Vol. 21, No. 6, 597-602 (2007)
DOI: 10.1177/0269881106070424
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